Summary - Project A: The goals of this research project are to design and discover novel peptide and peptidomimetic ligands that are multivalent ligands that can act as agonists at the mu and delta opioid receptors and antagonists at the neurokinin-1 (NK-1) receptor, all in a single molecule. These ligands can act as potent analgesics in chronic pain states, including neuropathic pain, using new mechanisms of action, but do not have any of the toxic side effects of current opioids. For this purpose, we are developing a comprehensive approach that includes: computer aided design of novel multivalent ligands, asymmetric synthesis of novel amino acids, design and synthesis of peptides and peptidomimetics with unique conformational properties, especially in membrane environments, unique biological properties for treatment of pain without toxicities and tolerance development, and unique abilities to penetrate membrane barriers. We will pursue these goals, with the following Specific Aims: 1) to design and synthesize novel multivalent ligands that have potent mu and delta opioid receptor agonist activity neutral and (mu preferring) and potent NK-1 receptor antagonist activity; 2) in conjunction with the Biochemical Core, to evaluate the pharmacological activities of these compounds with comprehensive binding affinities and efficacies at mu, delta and NK-1 receptors (also as needed, kappa opioid receptors and NK-3 receptors); 3) to evaluate the conformational properties of the best ligands by biophysical studies (NMR, CD, etc.) in aqueous and membrane environments; 4) in conjunction with the Biochemical and Synthesis Cores, to evaluate their biological activities in vivo to demonstrate the potency and efficacy in in vivo models of acute, prolonged and neuropathic pain states, and determine their lack of toxic side effects that are found in current analgesic drugs, including inhibition of gut transit, emesis, development of addictive behaviors, lack of respiratory depression and development of tolerance. We also will evaluate their ability to cross membrane barriers and their stability and biodistribution in vivo. A major goal is to obtain two or three potent, stable and bioavailable ligands with the desired biological activity profiles for examination in human clinical trials.